Melanoma – Targeted Therapies

Melanoma is the most virulent form of skin cancer with a rapidly rising incidence due to prior sun exposure. About 40,000 men and 30,000 women per year in the USA develop melanoma. In addition to sun exposure, there are independent genetic risk factors such as a variation in the “red hair” gene that increases in frequency the further one’s ancestral home is north of Africa.

Melanoma is the most virulent form of skin cancer with a rapidly rising incidence due to prior sun exposure. About 40,000 men and 30,000 women per year in the USA develop melanoma. In addition to sun exposure, there are independent genetic risk factors such as a variation in the “red hair” gene that increases in frequency the further one’s ancestral home is north of Africa.

Melanoma, as with all cancers, has its own genotype variations. There are at least five melanoma genotypes which can be detected with molecular profiling (for more information look at Vanderbilt’s “My cancer genome”). Each type has its own different mutations.

Just fewer than 50% of melanomas have a mutation in BRAF, a cell signaling pathway. Approximately 90% of the BRAF mutations produce a substitution of glutamic acid for valine at codon 600 in the gene product. This is apparently a critical factor in the development and aggressiveness of melanoma cells. About 20% of melanomas have an NRAS mutation, 1% have both BRAF and NRAS and 30% have neither mutation. Interestingly, among patients 20-30 years old, 86% will have the BRAF mutation but only 22% of those over 70 years have it. As a result, the new drugs that target the BRAF mutation gene product will be of relatively more utility in younger than in older individuals. One of the new targeted drugs is an inhibitor of the BRAF mutated gene product called Vemurafenib – the name based on “V600E mutated BRAF inhibitor.” Vemurafenib (Zelboraf) decreased the relative risk of death by 63% and the risk of tumor progression by 74% when combined with dacarbazine (an alkylating agent also known as DTIC or imidazole carboxamide which has been the long time standard of care for metastatic melanoma) compared to dacarbazine alone in a large cohort of patients with the BRAF V600E mutation in their melanoma. The FDA approved this drug for treating melanoma in August, 2011 for BRAF mutation positive patients as determined with a companion diagnostic device called the BRAF V600 Mutation Test. In this phase 3 trial of 675 patients, there as 48% response rate and a 5.3 month median progression free survival with Vemurafenib compared with dacarbazine with its 5% response rate and 1.6 month progression free survival median. Exciting as this sounds, it is no panacea and certainly not a cure although some patients had both excellent tumor shrinkage and long survivals, both rarely seen with dacarbazine. Side effects were acceptable but squamous cell skin cancers developed in some and activity declined over time. To deal with the latter, new trials are evaluating combined targeted therapy by adding a MEK gene product inhibitor. In early results, there was increased activity and fewer skin tumors developing.The cost, according to the manufacturer, Genentech, will be about $60,000 for a course of therapy over about six months. Vemurafenib tends to have rapid responses and so might be especially important for patients with extensive disease or severe symptoms. Despite the enthusiasm for a drug that actually has real benefit, it is not curative therapy nor does it produce truly long lasting responses. Still it is a major improvement and offers real benefits and hope to patients, a testament to the concept of targeted therapy based on genomic information. Another drug, ipilimumab (Yervoy) also has shown substantial activity against metastatic melanoma. Ipilimumab is a monoclonal antibody that binds to the cytotoxic T-lymphocyte antigen 4 (CTLA 4) and acts to enhance T-cell activation. In other words, it activates the immune system. It was approved by the FDA in March, 2011. The basic clinical trial that led to approval had 502 poor prognosis patients yet with good performance status. Patients randomized to ipilimumab plus dacarbazine had a longer time of progression free survival and the responses that developed persisted longer (19.3 vs. 8.1 months) than those who received dacarbazine alone. Overall survival was 11.2 months compared to 9.1 months but there were about 25% alive at four years which is quite noteworthy. Unfortunately, it can cause or exacerbate autoimmune disease because it allows T-cells to stay activated. The manufacturer, Bristol Meyers Squibb, at the request of the FDA, has sent a booklet to all medical oncologists to guide attention to these potentially serious side effects. It costs about $120,000 for a course of treatment.

So these are encouraging improvements for a tumor that has been exceptionally resistant to new approaches to treatment over the years. The key has been to understand the genetic mutations in the tumor, then to analyze the gene product and finally to create a drug that inhibits the gene product’s activity – genomic targeted therapy. Going forward, treatment will probably be a combination of compounds that interact with various mutations’ effects, hopefully augmenting the activity shown by these two drugs to date.